Numerous metabolic bone disorders are known to the medical community which are characterized by loss of bone mass or disproportionate mineralization of bone. These disorders include postmenopausal osteoporosis, senile osteoporosis, renal osteodystrophy, corticosteroid-induced osteopenia, and anticonvulsant osteomalacia. Of these disorders, postmenopausal and senile osteoporosis are most commonly encountered in normal medical practice.
As a group, these bone depletive disorders are a major and growing public health problem in the United States. Together, they cause more than 1 million bone fractures per year, primarily of the spine, hip, and distal forearm, and result in an annual cost of $6 or 7 billion to the American society. Unfortunately, the incidence of these bone disorders will rise significantly as the mean age of the U.S. population continues to increase.
Despite differing etiologies, the aforementioned metabolic bone disorders develop during an extended period of negative calcium balance. This commonality of the disorders suggests that agents which stimulate intestinal calcium absorption may be effective in restoring calcium balance and thereby treating or preventing the development of such bone disorders. It has long been known that Vitamin D plays a critical role in stimulating calcium absorption and regulating calcium metabolism. The discovery of the active forms of Vitamin D, [M. F. Holick et al., Proc. Natl. Acad. Sci. USA 68, 803-804 (1971); G. Jones et al., Biochemistry 14, 1250-1256 (1975)] and active Vitamin D analogues [M. F. Holick et al., Science 180, 190-191 (1973); H. Y. Lam et al., Science 186, 1038-1040 (1974)], caused much excitement and speculation about the usefulness of these compounds in the treatment of bone depletive disorders.
Animal studies examining the effects of these active Vitamin D compounds suggested that such agents would be useful in restoring calcium balance. Further, an early clinical study indicated that administration of 0.5 .mu.g/day of 1,25-dihydroxycholecalciferol (1,25 Vitamin D.sub.3) to a group of postmenopausal women improved the intestinal calcium absorption as well as the calcium balance of these women. On this basis, U.S. Pat. No. 4,225,596 ("'596 Patent") described and claimed the use of 1,25 Vitamin D.sub.3 for increasing calcium absorption and retention. Such use also was claimed in the same patent for 1,25 dihydroxyergocalciferol (1,25 Vitamin D.sub.2) and 1.alpha.-hydroxyergocalciferol (1.alpha.-Vitamin D.sub.2), which the patent teaches are "eminently suitable and readily substitutable for the 1,25 dihydroxycholecalciferol."
The best indicator of the efficacy of Vitamin D compounds to prevent or treat depletive bone disorders is bone itself rather than calcium absorption or calcium balance. More recent clinical data indicates that at the dosage ranges taught in the '596 Patent, 1,25 Vitamin D.sub.3 has, at best, modest efficacy in preventing or restoring loss of bone mass or bone mineral content [S. M. Ott and C. H. Chesnut, In: J. Jensen et al., eds., Norhaven A/S, Viborg, p. 83 (1987); J. C. Gallagher et al., 7th Workshop on Vitamin D, Rancho Mirage, p. 196 (1988); J. Aloia et al., Amer. J. Med. 84:401-408 (1988)].
Together these clinical studies with 1,25 Vitamin D.sub.3, and one other conducted with 1.alpha.-Vitamin D.sub.3 [M. Shiraki et al., Endocrinol. Japan 32,305-315 (1985)], indicate that the ability of these agents to restore lost bone mass or bone mineral content is dose related. These studies also indicate, however, that at the dosage ranges required for the agents to be truly effective, toxicity in the form of hypercalcemia and hypercalciuria becomes a major problem. Thus, attempts to increase the amount of 1,25 Vitamin D.sub.3 above 0.5 .mu.g/day have frequently resulted in toxicity. At dosage levels below 0.5 .mu.g/day no effects are observed on bone. [See G. F. Jensen et al., Clin. Endocrinol. 16, 515-524 (1982); C. Christiansen et al., Eur. J. Clin. Invest. 11, 305-309 (1981)]. Two .mu.g/day of 1.alpha.-Vitamin D.sub.3 was found to have efficacy in increasing bone mass in patients exhibiting senile osteoporosis [O. H. Sorensen et al., Clin. Endocrinol. 7, 169S- 175S (1977)]. Data from the clinical studies in Japan, a population that has low calcium intake, indicate that efficacy is found with 1.alpha.-Vitamin D.sub.3 when administered at 1 .mu.g/day [M..Shiraki et al., Endocrinol. Japan. 32:305-315 (1985); H. Orimo et al., Bone and Mineral 3, 47-52 (1987)]. At 2 .mu.g/day, however, toxicity with 1.alpha.-Vitamin D.sub.3 occurs in approximately 67 percent of the patients, and at 1 .mu.g/day this percentage is approximately 20 percent.
Thus, the prior art teaches that due to their toxicity, 1 hydroxylated Vitamin D compounds can only be administered at dosages that are, at best, modestly beneficial in preventing or treating loss of bone or bone mineral content. Indeed, Aloia recommends that alternative routes of administration be sought which might avoid the toxicity problems and allow higher dosage levels to be achieved. [J. Aloia et al , Amer. J. Med. 84:401-408 (1988)].